Heterocyclymethylpiperidines and -piperazines possessing affinity at 5ht-1 type receptors

ABSTRACT

Compounds of formula (I) and pharmaceutically acceptable salts thereof are disclosed: 
                         
wherein: A is optionally substituted phenyl, naphthyl, indolyl, quinolinyl, quinazolinyl, indazolyl, isoquinolinyl or benzofuranyl; X is carbon, Y is CH and
 
                         
is a double bond; or X is CH, Y is CH 2  or oxygen and
 
                         
is a single bond; or X is nitrogen, Y is CH 2  and
 
                         
is a single bond; R 1 is halogen, cyano, or C 1-6  alkoxy; a is 0,1, 2 or 3 ; b is 0 or 1 ; R 2 is hydrogen, C 1-6  alkyl, C 1-6  alkanoyl, fluoroC 1-6  alkanoyl, C 1-6  alkylsulfonyl, fluoroC 1-6  alkylsulfonyl, carbamoyl, C 1-6  alkylcarbamoyl or arylC 1-6  alkyl; and R 3 , together with the nitrogen atom to which it is attached, forms an optionally substituted 5 to 7 membered heterocyclic group fused to the benzene ring. Methods of preparing the compounds and uses of the compounds in therapy, in particular for a CNS disorder such as depression or anxiety, are also disclosed.

The present invention relates to novel compounds, processes for theirpreparation, pharmaceutical compositions containing the same and theiruse as medicaments in the treatment of CNS and other disorders.

A novel series of compounds has now been found that possess highaffinity for 5-HT₁ type receptors and/or are 5-HT reuptake inhibitors.The present invention therefore provides, in a first aspect, a compoundof formula (I) or a pharmaceutically acceptable salt thereof:

wherein:

-   A is optionally substituted phenyl, naphthyl, indolyl, quinolinyl,    quinazolinyl, indazolyl, isoquinolinyl or benzofuranyl,-   X is carbon, Y is CH and

is a double bond; or X is CH, Y is CH₂ or oxygen and

is a single bond; or X is nitrogen, Y is CH₂ and

is a single bond;

-   R1 is halogen, cyano, or C₁₋₆alkoxy;-   a is 0, 1,2or 3;-   b is 0 or 1;-   R2 is hydrogen, C₁₋₆alkyl, C₁₋₆alkanoyl, fluoroC₁₋₆alkanoyl,    C₁₋₆alkylsulfonyl, fluoroC₁₋₆alkylsulfonyl, carbamoyl,    C₁₋₆alkylcarbamoyl or arylC₁₋₆alkyl; and-   R3, together with the nitrogen atom to which it is attached, forms    an optionally substituted 5 to 7 membered heterocyclic group fused    to the benzene ring.

The term “halogen” and its abbreviation “halo” refer to fluorine,chlorine, bromine or iodine.

The term “C₁₋₆alkyl” refers to an alkyl group having from one to sixcarbon atoms, in all isomeric forms, such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl,sec-pentyl, n-pentyl, isopentyl, tert-pentyl and hexyl.

The term “C₁₋₆alkoxy” refers to a straight chain or branched chainalkoxy (or “alkyloxy”) group having from one to six carbon atoms, suchas methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,tert-butoxy, pentoxy, neopentoxy, sec-pentoxy, n-pentoxy, isopentoxy,tert-pentoxy and hexoxy.

The term “C₁₋₆alkanoyl” refers to an alkanoyl group having from 1 to 6carbon atoms, such as methanoyl (or “formyl”), ethanoyl (or “acetyl”),propanoyl, isopropanoyl, butanoyl, isobutanoyl, sec-butanoyl, pentanoyl,neopentanoyl, sec-pentanoyl, isopentanoyl, tertpentanoyl and hexanoyl.

The term “fluoroC₁₋₆alkanoyl” refers to a fluorine-substitutedC₁₋₆alkanoyl group such as CF₃CO. The term “fluoroC₁₋₆alkylsulfonyl”refers to a fluorine-substituted C₁₋₆alkylsulfonyl group such asCF₃SO₂—.

The term “carbamoyl” refers to the group H₂NCO. The term“C₁₋₆alkylcarbamoyl” refers to a group having the formula(C₁₋₆alkyl)HNCO, such as CH₃NHCO.

The term “aryl”, whether alone or as part of another group, is intended,unless otherwise stated, to denote an aromatic carbocyclic orheterocyclic group such as phenyl, naphthyl, pyridyl or pyrazinyl,optionally substituted by one or more halogen, C₁₋₆alkyl, CF₃, cyano,hydroxy, C₁₋₆alkanoyl, or C₁₋₆alkoxy. Where used herein the termnaphthyl, whether alone or as part of another group, is intended, unlessotherwise stated, to denote both 1-naphthyl and 2-naphthyl groups.

The term “oxo” refers to the group “═O”.

The term “optionally substituted 5 to 7 membered heterocyclic group”refers to an optionally substituted saturated or non-saturated ringcontaining at least one nitrogen atom and optionally a further 1 or 2heteroatoms selected from nitrogen, sulphur or oxygen, the ringconsisting of a total of 5 to 7 atoms. Examples of 5 to 7 memberedheterocyclic groups include pyrrolidinyl, imidazolidinyl, pyrazolidinyl,oxazolidinyl, isothiazolidinyl, thiazolidinyl, pyrrolyl, pyrrolinyl,pyrazolinyl, imidazolyl, pyrazolyl, isothiazolyl, thiazolyl, piperidyl,piperazinyl, morpholinyl, thiomorpholinyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, azepinyl and azepanyl. The heterocyclic groupmay be substituted by one or more, preferably 1 to 3, substituents,which may be the same or different, and which is selected from thefollowing group: oxo, C₁₋₆alkyl, cyano, CF₃, C₁₋₆alkoxy andC₁₋₆alkanoyl.

The term “C₃₋₇cycloalkylC₁₋₆alkoxy” refers to a cycloalkyl groupconsisting of from 3 to 7 carbon atoms (for example cyclopropane,cyclobutane, cyclopentane, cyclohexane and cycloheptane) attached to anarylC₁₋₆alkoxy group.

When b is two or more, the two or more R2 groups may be the same ordifferent.

A is optionally substituted phenyl, naphthyl, indolyl, quinolinyl,quinazolinyl, indazolyl, isoquinolinyl or benzofuranyl. These groups maybe attached to the oxygen atom in formula (I) at any suitable position.These groups may be substituted by 1 to 4 substituents, which may be thesame or different, and which are selected from the following group:halogen, hydroxy, cyano, CF₃, C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆alkoxyC₁₋₆alkyl, C₃₋₇cycloalkylC₁₋₆alkoxy, C₁₋₆alkanoyl,C₁₋₆alkylsulfonyl, C₁₋₆alkylsulfinyl, C₁₋₆alkylsulfonyloxy,C₁₋₆alkylsulfonylC₁₋₆alkyl, C₁₋₆alkylsulfonamido, C₁₋₆alkylamido,C₁₋₆alkylsulfonamidoC₁₋₆alkyl and C₁₋₆alkylamidoC₁₋₆alkyl. Preferredoptional substituents for A are C₁₋₆alkyl, cyano, CF₃, C₁₋₆alkoxy andC₁₋₆alkanoyl.

Preferably A is quinolinyl or quinazolinyl. Most preferably, A is5-(2-methyl)quinolinyl or 5-(2-methyl)quinazolinyl.

Preferably Y is CH₂ or CH.

Preferably R1 is fluoro.

Preferably a is 0, 1 or 2.

When b is 1, preferably R2 is hydrogen, C1-6alkyl (particularly methyl,ethyl or propyl) or C1-6alkylsulfonyl.

R3, together with the nitrogen atom to which it is attached, forms anoptionally substituted 5 to 7 membered heterocyclic group fused to thebenzene ring. As clear from formula (I), the heterocyclic ring is fusedto the benzene ring at the position which is ortho to both Y and to thenitrogen atom. Preferably, the optionally substituted 5 to 7 memberedheterocyclic group, together with the phenyl ring to which it isattached, forms an optionally substituted benzoxazinone,benzoimidazolyl, quinoxalinyl or quinolinyl group.

Preferred compounds of this invention are:

-   8-{1-[2-(2-Methylquinolin-5-yloxy)ethyl]piperidin-4-yloxy}-4H-benzo[1,4]oxazin-3-one    hydrochloride (E1)-   5-{2-[4-(3H-Benzimidazol-4-ylmethyl)piperazin-1-yl]ethoxy}-2-methylquinoline    (E2)-   5-{4-[2-(2-Methylquinolin-5-yloxy)ethyl]piperazin-1-ylmethyl}quinoline    (E3)-   5-{4-[2-(2-Methylquinolin-5-yloxy)ethyl]piperazin-1-ylmethyl}quinoxaline    (E4)-   8-{1-[2-(2-Methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}4H-benzo[1,4]oxazin-3-one    (E5)-   8-{1-[2-(7-Fluoro-2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}-4H-benzo[1,4]oxazin-3-one    (E6)-   8-{1-[2-(7-Chloro-2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}-4H-benzo[1,4]oxazin-3-one    (E7)-   8-{1-[2-(2-Methylquinazolin-5-yloxy)ethyl]piperidin-4-ylmethyl}-4H-benzo[1,4]oxazin-3-one    (E8)-   4-Methyl-8-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}-4H-benzo[1,4]oxazin-3-one    (E9)-   8-{1-[2-(7-Fluoro-2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}-4-methyl-4H-benzo[1,4]oxazin-3-one    (E10)-   8-{1-[2-(7-Chloro-2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}-4-methyl-4H-benzo[1,4]oxazin-3-one    (E11)-   4-Methyl-8-{1-[2-(2-methylquinazolin-5-yloxy)ethyl]piperidin-4-ylmethyl}-4H-benzo[1,4]oxazin-3-one    (E12)    and pharmaceutically acceptable salts thereof.

The compounds of formula (I) can form acid addition salts thereof. Itwill be appreciated that for use in medicine the salts of the compoundsof formula (I) should be pharmaceutically acceptable. Suitablepharmaceutically acceptable salts will be apparent to those skilled inthe art and include those described in J. Pharm. Sci., 1977, 66, 1–19,such as acid addition salts formed with inorganic acids e.g.hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid; andorganic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric,benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid.Certain of the compounds of formula (I) may form acid addition saltswith one or more equivalents of the acid. The present invention includeswithin its scope all possible stoichiometric and non-stoichiometricforms.

The compounds of formula (I) may be prepared in crystalline ornon-crystalline form, and, if crystalline, may optionally be hydrated orsolvated. This invention includes within its scope stoichiometrichydrates or solvates as well as compounds containing variable amounts ofwater and/or solvent.

Certain compounds of formula (I) are capable of existing instereoisomeric forms (e.g. geometric or (“cis-trans”) isomers,diastereomers and enantiomers) and the invention extends to each ofthese stereoisomeric forms and to mixtures thereof including racemates.The different stereoisomeric forms may be separated one from the otherby the usual methods, or any given isomer may be obtained bystereospecific or asymmetric synthesis. The invention also extends toany tautomeric forms and mixtures thereof. The present inventionincludes within its scope all such isomers, including mixtures.

In a further aspect, this invention provides a process for thepreparation of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof, which process comprises:

(a) the coupling of a compound of formula (II):

wherein A is as defined for formula (I) and L is a leaving group, with acompound of formula (III):

wherein a, b, R1, R2, R3, X, Y and

are as defined for formula (I);

-   or-   (b) for a compound wherein X is nitrogen, the coupling of a compound    of formula (IV):

wherein A is as defined for formula (I), with a compound of formula (V):

wherein a, b, R1, R2 and R3 are as defined for formula (I);

-   and thereafter optionally for process (a) or process (b):    -   removing any protecting groups and/or    -   converting a compound of formula (I) into another compound of        formula (I) and/or    -   forming a pharmaceutically acceptable salt.

For process (a), the reaction of compounds of formulae (II) and (III) ispreferably carried out in a suitable solvent such as isopropyl alcoholor N,N-dimethylformamide, in the presence of an appropriate base such asN,N-diisopropylethylamine or potassium carbonate. A suitable leavinggroup L is bromine.

For process (b), the reaction of compounds of formulae (IV) and (V) ispreferably carried out in an aprotic solvent such as 1,2-dichloroethane,in the presence of an appropriate reducing agent such as sodiumtriacetoxyborohydride.

Compounds of formula (I) can be converted into further compounds offormula (I) using standard techniques. For example, and by way ofillustration rather than limitation, for compounds of formula (I)wherein

is a double bond can be converted to compounds of formula (I) in which

is a single bond by palladium catalysed hydrogenation in a suitablesolvent such as ethanol. Other possible conversion reactions includeacylation with an appropriate acylating agent such as acetyl chloride,alkylation using an appropriate alkylating reagent such as methyliodide, and sulfonylation using a sulfonylating agent such asmethanesulfonic anhydride.

Compounds of formulae (II), (III), (IV) and (V) are commerciallyavailable, may be prepared according to procedures described herein, byknown literature methods, or by analogous procedures thereto.

For example, for compounds of the present invention wherein X is carbon,Y is CH and

is a double bond, compounds of formula (III) wherein X is carbon may beprepared by reacting a compound of formula (VI):

wherein “Alk” refers to an alkyl group, with a compound of formula(VII):

wherein Q is a protecting group such as t-butyloxycarbonyl, in thepresence of a base such as sodium hydride, in a solvent such astetrahydrofuran or N,N-dimethylformamide. The protecting group Q may beremoved thereafter by any suitable means.

Compounds of formula (VI) may be prepared by treating a compound offormula (VIII):

wherein L is a leaving group such as bromine, with a trialkyl phosphitesuch as triethyl phosphite or trimethyl phosphite, in the absence ofsolvent or in the presence of a solvent such as toluene.

It will be appreciated by those skilled in the art that it may benecessary to protect certain reactive substituents during some of theabove procedures. Standard protection and deprotection techniques, suchas those described in Greene T. W. Protective groups in organicsynthesis, New York, Wiley (1981), can be used. For example, primaryamines can be protected as phthalimide, benzyl, t-butyloxycarbonyl,benzyloxycarbonyl or trityl derivatives. Carboxylic acid groups can beprotected as esters. Aldehyde or ketone groups can be protected asacetals, ketals, thioacetals or thioketals. Deprotection of such groupsis achieved using conventional procedures well known in the art. Forexample, protecting groups such as t-butyloxycarbonyl may be removedusing an acid such as hydrochloric or trifluroroacetic acid in asuitable solvent such as dichloromethane, diethylether, isopropanol ormixtures thereof.

Pharmaceutically acceptable salts may be prepared conventionally byreaction with the appropriate acid or acid derivative.

The affinities of the compounds of this invention for 5-HT_(1A),5-HT_(1B) and 5-HT_(1D) receptors can be determined by the radioligandbinding assay as described in WO 99/07700. All compounds testedaccording to the radioligand binding assay described above were found tohave pKi values >6.0 at 5-HT_(1A), 5-HT_(1B) and 5-HT_(1D) receptors,with many showing a considerably higher affinity (having pKi values inthe range 8.0–10.0).

The intrinsic activity of the compounds of this invention can bedetermined according to the [³⁵S]GTPγS functional assay which is alsodescribed in WO 99/07700. It has been found, using the [³⁵S]GTPγSfunctional assay, that certain compounds of formula (I) appear to beantagonists at 5-HT₁ type receptors whilst others appear to be inverseagonists, agonists or partial agonists.

The efficacy of the compounds of this invention to inhibit the re-uptakeof serotonin can be measured in a 5-HT uptake assay by measurement ofuptake of [³H]-5-HT into rat cortical synaptosomes as described inThomas, D. R.; Nelson, D. R.; and Johnson, A. M. Psychopharmacology93:193–200 (1987). Some of the compounds of the present invention weretested according to this 5-HT uptake assay and were found to havepotency at the uptake site of pKi>6.0. Some compounds tested had a pKivalue of >8.0.

Concomitant blockade of 5-HT_(1A), 5-HT_(1B) and 5-HT_(1D) autoreceptorsor alternatively blockade of 5-HT_(1A), 5-HT_(1B) and 5-HT_(1D)autoreceptors, in addition to the blockade of serotonin reuptaketransporter, has been found to elevate synaptic 5-HT and increaseserotonergic transmission, and acutely mimic the effects of chronictreatment with SSRIs. This is expected to result in advantages ofincreased efficacy, faster onset and a favourable side-effect profile inthe clinic.

Compounds of formula (I) and their pharmaceutically acceptable salts areof use in the treatment of certain CNS disorders such as depression(both bipolar and unipolar), single or recurrent major depressiveepisodes with or without psychotic features, catatonic features,melancholic features, atypical features or postpartum onset, seasonalaffective disorder and dysthymia, anxiety disorders, includinggeneralised anxiety, schizophrenia, panic disorder, agoraphobia, socialphobia, obsessive compulsive disorder and post-traumatic stressdisorder; pain (particularly neuropathic pain); memory disorders,including dementia, amnesic disorders and age-associated memoryimpairment; disorders of eating behaviours, including anorexia nervosaand bulimia nervosa, sexual dysfunction, sleep disorders (includingdisturbances of circadian rhythm, dyssomnia, insomnia, sleep apnea andnarcolepsy), withdrawal from abuse of drugs such as of cocaine, ethanol,nicotine, benzodiazepines, alcohol, caffeine, phencyclidine(phencyclidine-like compounds), opiates (e.g. cannabis, heroin,morphine), sedative ipnotic, amphetamine or amphetamine-related drugs(e.g. dextroamphetamine, methylamphetamine) or a combination thereof,motor disorders such as Parkinson's disease, dementia in Parkinson'sdisease, neuroleptic-induced Parkinsonism and tardive dyskinesias, aswell as other psychiatric disorders. Depressive disorders which may betreated or prevented by the compounds of formula (I) and theirpharmaceutically acceptable salts may also result from a general medicalcondition including, but not limited to, myocardial infarction,diabetes, miscarriage or abortion, etc. Compounds of formula (I) mayalso have utility in the treatment of certain gastrointestinal disorderssuch as irritable bowel syndrome.

It is to be understood that “treatment” as used herein includesprophylaxis as well as alleviation of established symptoms.

Thus the invention also provides a compound of formula (I) or apharmaceutically acceptable salt thereof, for use as a therapeuticsubstance, in particular in the treatment of the above disorders. Inparticular the invention provides a compound of formula (I) or apharmaceutically acceptable salt thereof for use as a therapeuticsubstance in the treatment of a CNS disorder, particularly depression oranxiety.

Compounds of the invention may be administered in combination with otheractive substances such as 5HT3 antagonists, serotonin agonists, NK-1antagonists, selective serotonin reuptake inhibitors (SSRI),noradrenaline re-uptake inhibitors (SNRI), tricyclic antidepressantsand/or dopaminergic antidepressants.

Suitable 5HT3 antagonists which may be used in combination of thecompounds of the inventions include for example ondansetron,granisetron, metoclopramide.

Suitable serotonin agonists which may be used in combination with thecompounds of the invention include sumatriptan, rauwolscine, yohimbine,metoclopramide.

Suitable SSRIs which may be used in combination with the compounds ofthe invention include fluoxetine, citalopram, femoxetine, fluvoxamine,paroxetine, indalpine, sertraline, zimeldine.

Suitable SNRIs which may be used in combination with the compounds ofthe invention include venlafaxine and reboxetine.

Suitable tricyclic antidepressants which may be used in combination witha compound of the invention include imipramine, amitriptiline,chlomipramine and nortriptiline.

Suitable dopaminergic antidepressants which may be used in combinationwith a compound of the invention include bupropion and amineptine.

It will be appreciated that the compounds of the combination orcomposition may be administered simultaneously (either in the same ordifferent pharmaceutical formulations), separately or sequentially.

The invention further provides a method of treatment of the abovedisorders, particularly a CNS disorder such as depression or anxiety, inmammals including humans, which comprises administering to the sufferera therapeutically safe and effective amount of a compound of formula (I)or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides for the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof in themanufacture of a medicament for use in the treatment of the abovedisorders, particularly a CNS disorder such as depression or anxiety.

In order to use the compounds of formula (I) in therapy, they willnormally be formulated into a pharmaceutical composition in accordancewith standard pharmaceutical practice. The present invention alsoprovides a pharmaceutical composition, which comprises a compound offormula (I) or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier or excipient.

In a further aspect, the present invention provides a process forpreparing a pharmaceutical composition, the process comprising mixing acompound of formula (I) or a pharmaceutically acceptable salt thereofand a pharmaceutically acceptable carrier or excipient.

A pharmaceutical composition of the invention, which may be prepared byadmixture, suitably at ambient temperature and atmospheric pressure, isusually adapted for oral, parenteral or rectal administration and, assuch, may be in the form of tablets, capsules, oral liquid preparations,powders, granules, lozenges, reconstitutable powders, injectable orinfusible solutions or suspensions or suppositories. Orallyadministrable compositions are generally preferred.

Tablets and capsules for oral administration may be in unit dose form,and may contain conventional excipients, such as binding agents (e.g.pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose orcalcium hydrogen phosphate); tabletting lubricants lubricants (e.g.magnesium stearate, talc or silica); disintegrants (e.g. potato starchor sodium starch glycollate); and acceptable wetting agents (e.g. sodiumlauryl sulphate). The tablets may be coated according to methods wellknown in normal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspension, solutions, emulsions, syrups or elixirs, or may be inthe form of a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents (e.g. sorbitol syrup,cellulose derivatives or hydrogenated edible fats), emulsifying agents(e.g. lecithin or acacia), non-aqueous vehicles (which may includeedible oils e.g. almond oil, oily esters, ethyl alcohol or fractionatedvegetable oils), preservatives (e.g. methyl or propyl-p-hydroxybenzoatesor sorbic acid), and, if desired, conventional flavourings or colorants,buffer salts and sweetening agents as appropriate. Preparations for oraladministration may be suitably formulated to give controlled release ofthe active compound.

For parenteral administration, fluid unit dosage forms are preparedutilising a compound of the invention or pharmaceutically acceptablesalt thereof and a sterile vehicle. Formulations for injection may bepresented in unit dosage form e.g. in ampoules or in multi-dose,utilising a compound of the invention or pharmaceutically acceptablesalt thereof and a sterile vehicle, optionally with an addedpreservative. The compositions may take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilising and/or dispersingagents.

Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g. sterile pyrogen-free water,before use. The compound, depending on the vehicle and concentrationused, can be either suspended or dissolved in the vehicle. In preparingsolutions, the compound can be dissolved for injection and filtersterilised before filling into a suitable vial or ampoule and sealing.Advantageously, adjuvants such as a local anaesthetic, preservatives andbuffering agents are dissolved in the vehicle. To enhance the stability,the composition can be frozen after filling into the vial and the waterremoved under vacuum. Parenteral suspensions are prepared insubstantially the same manner, except that the compound is suspended inthe vehicle instead of being dissolved, and sterilisation cannot beaccomplished by filtration. The compound can be sterilised by exposureto ethylene oxide before suspension in a sterile vehicle.Advantageously, a surfactant or wetting agent is included in thecomposition to facilitate uniform distribution of the compound.

Lotions may be formulated with an aqueous or oily base and will ingeneral also contain one or more emulsifying agents, stabilising agents,dispersing agents, suspending agents, thickening agents, or colouringagents. Drops may be formulated with an aqueous or non-aqueous base alsocomprising one or more dispersing agents, stabilising agents,solubilising agents or suspending agents. They may also contain apreservative.

The compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g. containingconventional suppository bases such as cocoa butter or other glycerides.

The compounds of the invention may also be formulated as depotpreparations. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds of theinvention may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

For intranasal administration, the compounds of the invention may beformulated as solutions for administration via a suitable metered orunitary dose device or alternatively as a powder mix with a suitablecarrier for administration using a suitable delivery device. Thuscompounds of formula (I) may be formulated for oral, buccal, parenteral,topical (including ophthalmic and nasal), depot or rectal administrationor in a form suitable for administration by inhalation or insufflation(either through the mouth or nose).

The compounds of the invention may be formulated for topicaladministration in the form of ointments, creams, gels, lotions,pessaries, aerosols or drops (e.g. eye, ear or nose drops). Ointmentsand creams may, for example, be formulated with an aqueous or oily basewith the addition of suitable thickening and/or gelling agents.Ointments for administration to the eye may be manufactured in a sterilemanner using sterilised components.

The composition may contain from 0.1% to 99% by weight, preferably from10 to 60% by weight, of the active material, depending on the method ofadministration. The dose of the compound used in the treatment of theaforementioned disorders will vary in the usual way with the seriousnessof the disorders, the weight of the sufferer, and other similar factors.However, as a general guide suitable unit doses may be 0.05 to 1000 mg,more suitably 1.0 to 200 mg, and such unit doses may be administeredmore than once a day, for example two or three times a day. Such therapymay extend for a number of weeks or months.

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

The following Descriptions and Examples illustrate the preparation ofcompounds of the invention.

Description 1

tert-Butyl 4-[2-(2-methylquinolin-5-yloxy)ethyl]piperazine-1-carboxylate(D1)

tert-Butyl piperazine-1-carboxylate (1.4 g, 7.52 mmol) was added to amixture of 5-(2-bromoethoxy)-2-methylquinoline (2 g, 7.52 mmol) andpotassium carbonate (4.16 g, 30.1 mmol) in N,N-dimethylformamide (20mL). The reactants were heated at 70° C. for 16 h under an atmosphere ofargon. The reaction mixture was poured into water (200 mL) and extractedinto ethyl acetate (3×200 mL). The organic layers were combined, dried(Na₂SO₄) and concentrated in vacuo. The residue was purified by columnchromatography, eluting with 30% ethyl acetate in hexane affording thetitle compound as a tan solid (1.04 g, 37%).

Mass spectrum (API⁺): Found 372.3 (MH⁺). C₂₁H₂₉N₃O₃ requires 371. ¹H NMR(CDCl₃) δ: 1.46 (9H, s), 2.59 (4H, t), 2.73 (3H, s), 2.96 (2H, t), 3.46(4H, t), 4.29 (2H, t), 6.80 (1H, dd), 7.26 (1H, d), 7.58 (2H, m), 8.43(1H, d).

Description 2

2-Methyl-5-(2-piperazin-1-ylethoxy)quinoline (D2)

tert-Butyl 4-[2-(2-methylquinolin-5-yloxy)ethyl]piperazine-1-carboxylate(1.04 g, 2.8 mmol) was dissolved in ethanol (60 mL) and treated with 1Mhydrochloric acid in diethyl ether (16 mL, 16 mmol) and stirred at 40°C. for 17 h. The reaction mixture was filtered and the white solid wascollected and dried in vacuo. The hydrochloride salt precipitate wasdissolved in water (25 mL) and potassium carbonate was added until thepH reached 10. The aqueous layer was washed with 5% methanol indichloromethane (4×100 mL) then 10% methanol in dichloromethane (4×100mL). The organic layers were combined, dried (Na₂SO₄) and concentratedin vacuo, affording the title compound as a brown oil (0.69 g, 91%).

Mass spectrum (API⁺): Found 272 (MH⁺). C₁₆H₂₁N₃O requires 271.

¹H NMR (CDCl₃, free base) δ: 2.62 (4H, m), 2.73 (3H, s), 2.92 (6H, m),3.47 (1H, s), 4.29 (2H, d), 6.80 (1H, dd), 7.50 (1H, d), 7.58 (2H, m),8.45 (1H, d).

Description 3

5-Bromo-2-methoxy-3-nitrobenzaldehyde (D3)

5-Bromo-2-methoxybenzaldehyde (29.65 g, 138 mmol) was added to stirredconcentrated sulfuric acid (160 mL) at −15° C. Nitric acid (70% w/w) (16g) was added dropwise. Further stirring was allowed for 15 mins at thistemperature before the mixture was poured onto crushed ice (2 L). Theresulting precipitate was collected by filtration and partitionedbetween dichloromethane (800 mL) and saturated sodium hydrogen carbonate(1 L). The organic layer was dried (Na₂SO₄) and evaporated in vacuo togive the title compound (20.5 g) as a crude solid.

¹H NMR (CDCl₃) δ: 4.08 (3H, s), 8.17–8.22 (2H, m), 10.32 (1H, s).

Description 4

5-Bromo-2-methoxy-3-nitrobenzyl Alcohol (D4)

Sodium borohydride (4 g) was added in portions to a stirring solution ofcrude 5-bromo-2-methoxy-3-nitrobenzaldehyde (20.5 g) in methanol (350mL) and tetrahydrofuran (150 mL) at 0° C. After 1 h, the methanol wasremoved in vacuo. The residue was treated with cold water (150 mL) andextracted with diethyl ether (2×150 mL). The combined organic layer wasevaporated in vacuo to give a crude oil. Silica gel chromatographyeluting with ethyl acetate in petroleum ether (10–40%) gave the titlecompound (17 g) as a solid.

¹H NMR (CDCl₃) δ: 2.00 (1H, t, J=6 Hz), 3.92 (3H, s), 4.80 (2H, d, J=6Hz), 7.84 (1H, d, J=2 Hz), 7.91 (1H, d, J=2 Hz).

Description 5

5-Bromo-2-methoxy-3-nitrobenzyl Bromide (D5)

2,6-Lutidine (10.5 mL) was added to a stirring solution of5-bromo-2-methoxy-3-nitrobenzyl alcohol (13.6 g) and lithium bromide(11.75 g) in anhydrous tetrahydrofuran (200 mL) at 0° C. A solution ofmethanesulfonic anhydride (11.8 g) in anhydrous tetrahydrofuran (20 mL)was added dropwise. The resulting mixture was left to stir at roomtemperature for 16 h. It was partitioned between diethyl ether (250 mL)and saturated sodium hydrogen carbonate (150 mL). The organic layer wasdried (sodium sulfate) and evaporated in vacuo. Silica gelchromatography of the crude residue eluting with diethyl ether inpetroleum ether gave the title compound (20 g) as an amber oil.

¹H NMR (CDCl₃) δ: 4.06 (3H, s), 4.48 (2H, s), 7.76 (1H, d, J=2 Hz), 7.93(1H, d, J=2 Hz).

Description 6

tert-Butyl4-(5-bromo-2-methoxy-3-nitrobenzylidene)piperidine-1-carboxylate (D6)

A mixture of 5-bromo-2-methoxy-3-nitrobenzyl bromide (8.4 9, 26 mmol)and triethyl phosphite (4.5 g, 27 mmol) was heated to 160° C. for 2 hand then evaporated in vacuo to give a dark amber oil. This wasdissolved in anhydrous tetrahydrofuran (20 mL) and added dropwise to astirring suspension of sodium hydride (60%) (1.14 g) in anhydrousN,N-dimethylformamide (100 mL) at 0° C. The mixture was left to stir for1 hour. tert-Butyl 4-oxopiperidine-1-carboxylate (5.17 g, 26 mmol) inanhydrous THF (30 mL) was added to the mixture. Stirring was continuedfor 4 h at room temperature before the mixture was poured into saturatedammonium chloride (100 mL) and extracted with diethyl ether (2×150 mL).The combined organic layer was evaporated in vacuo to give a crude oil.Silica gel chromatography eluting with diethyl ether in petroleum ether(5–30%) gave the title compound (3.9 g, 35%) as an oil.

¹H NMR (CDCl₃) δ: 1.48 (9H, s), 2.25–2.45 (4H, m), 3.35–3.58 (4H, m),3.84 (3H, s), 6.29 (1H, s), 7.46 (1H, d, J=2 Hz), 7.79 (1H, d, J=2 Hz).

Description 7

tert-Butyl4-(5-bromo-2-hydroxy-3-nitrobenzylidene)piperidine-1-carboxylate (D7)

A mixture of tert-butyl4-(5-bromo-2-methoxy-3-nitrobenzylidene)piperidine-1-carboxylate (2.5 g,5.9 mmol) and lithium chloride (1 g) in anhydrous N,N-dimethylformamidewas stirred at 120° C. for 4 h. It was allowed to cool to roomtemperature and evaporated in vacuo. The residue was treated with water(50 mL) and extracted with diethyl ether (2×100 mL). The combinedorganic layers was washed with water (50 mL) and dried (Na₂SO₄).Evaporation of solvent gave the title compound as a crude oil (2.1 g).

¹H NMR (CDCl₃) δ: 1.48 (9H, s), 2.20–2.40 (4H, m), 3.34–3.55 (4H, m),6.25 (1H, s), 7.43 (1H, s), 7.76 (1H, s).

Description 8

tert-Butyl4-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-ylmethyl)piperidine-1-carboxylate(D8)

A solution of tert-butyl4-(5-bromo-2-hydroxy-3-nitrobenzylidene)piperidine-1-carboxylate (2.1 g,4.9 mmol) in methanol (150 mL) was stirred under atmospheric hydrogen inthe presence of 10% palladium on charcoal (0.5 g) for 4 h. The catalystwas removed by filtration and the filtrate was evaporated in vacuo togive a crude oil (1.8 g) which was taken up in 2-butanone (30 mL) andaqueous sodium hydrogen carbonate (1.3 g in water 20 mL). Chloroacetylchloride (0.78 g) was added dropwise at 0° C. The mixture was stirred at0° C. for further 2 h and then at 80° C. for 4 h. It was partitionedbetween water (50 mL) and ethyl acetate (100 mL). The organic layer wasevaporated in vacuo. Silica gel chromatography of the resulting residueeluting with ethyl acetate in petroleum ether (20–30%) gave the titlecompound (1.5 g) as an oil.

¹H NMR (CDCl₃) δ: 1.10–1.20 (2H, m), 1.45 (9H, s), 1.55–1.64 (2H, m),1.64–1.74 (1H, m), 2.56 (2H, d, J=8 Hz), 2.57–2.76 (2H, m), 4.00–4.15(2H, m), 4.60 (2H, s), 6.64 (1H, d, J=8 Hz), 6.80 (1H, d, J=8Hz), 6.88(1H, t, J=8 Hz), 7.60 (1H, s).

Description 9

tert-Butyl4-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-ylmethyl)piperidine-1-carboxylate(D9)

A solution of tert-butyl4-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-ylmethyl)piperidine-1-carboxylate(0.6 g, 1.73 mmol) in anhydrous N,N-dimethylformamide (1 mL), was addeddropwise to a stirred suspension of sodium hydride (60%) (0.08 g) inanhydrous N,N-dimethylformamide (12 mL) at 0° C. Stirring was continuedfor a further 20 mins. before iodomethane (0.5 g) in anhydrousN,N-dimethylformamide (1 mL) was added. The mixture was allowed to stirat room temperature for 4 hours. It was quenched with saturated ammoniumchloride (20 mL) and extracted with diethyl ether (100 mL). The organiclayer was dried (Na₂SO₄) and evaporated in vacuo to give a crude oil.Silica gel chromatography eluting with ethyl acetate in hexane (10–20%)gave the title compound as a solid (0.6 g, 97%).

¹H NMR (CDCl₃) δ: 1.10–1.20 (2H, m), 1.45 (9H, s), 1.53–1.75 (3H, m),2.57 (2H, d, J=8 Hz), 2.58–2.70 (2H, m), 3.36 (3H, s), 3.96–4.15 (2H,m), 4.58 (2H, s), 6.84 (2H, m), 6.96 (1H, t, J=8 Hz).

Description 10

8-(Piperidin-4-ylmethyl)-4H-benzo[1,4]oxazin-3-one (D10)

The title compound was prepared from tert-butyl4-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-ylmethyl)piperidine-1-carboxylatefollowing the method of Description 2.

Description 11

4-Methyl-8-(piperidin-4-ylmethyl)-4H-benzo[1,4]oxazin-3-one (D11)

The title compound was prepared from tert-butyl4-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-ylmethyl)piperidine-1-carboxylatefollowing the method of Description 2.

Description 12

5-Fluoro-2-methyl-3,4-dihydroquinazoline (D12)

A solution of 2-amino-6-fluorobenzylamine (1.1 g, 7.86 mmol) andtriethylorthoacetate (1.58 mL, 8.64 mmol) in ethanol (30 mL) was heatedat 80° C. for 14 h. The reaction mixture was allowed to cool to roomtemperature and evaporated in vacuo. The yellow oil was triturated withdiethyl ether to give the title compound as white solid (0.74 g, 57%).

Mass spectrum (API⁺): Found 165 (MH⁺). C₉H₉N₂F requires 164.

¹H NMR (CDCl₃) δ: 2.02 (3H, s), 4.67 (2H, s), 6.34–6.71 (2H, m),7.03–7.12 (1H, m).

Description 13

5-Fluoro-2-methylquinazoline (D13)

To a solution of 5-fluoro-2-methyl-3,4-dihydroquinazoline (0.74 g, 4.51mmol) in chloroform (100 mL) at room temperature was added manganese(IV) oxide (4.0 g, 46.0 mmol) and the reaction mixture stirred at roomtemperature for 20 h. The reaction mixture was filtered through a plugof celite, washing with dichloromethane. The filtrate was evaporated invacuo to give the title compound as a yellow solid (0.715 g, 98%).

Mass spectrum (API⁺): Found 163 (MH⁺). C₉H₇N₂F requires 162.

¹H NMR (CDCl₃) δ: 2.92 (3H, s), 7.19–7.27 (1H, m), 7.77–7.83 (2H, m),9.60 (1H, s).

Description 14

2-(2-Methylquinazolin-5-yloxy)ethanol (D14)

To a solution of ethylene glycol (3.05 mL, 55.6 mmol) inN,N-dimethylformamide (50 mL) at room temperature was added sodiumhydride (60% dispersion in oil, 0.30 g, 7.50 mmol) portion-wise. Thereaction mixture was allowed to stir at room temperature for 30 minutes.A solution of 5-fluoro-2-methylquinazoline (2.22 g, 55.6 mmol) inN,N-dimethylformamide (5 mL) was added and the reaction mixture heatedat 85° C. for 14 h. The mixture was allowed to cool to room temperature,quenched by the addition of water and concentrated in vacuo.Chromatography of the residue on SiO₂ eluting with 40% ethyl acetate indichloromethane to ethyl acetate gave the title compound as a yellowsolid (0.39 g, 10%).

Mass spectrum (API⁺): Found 205 (MH⁺) C₁₁H₁₂N₂O₂ requires 204.

¹H NMR (CDCl₃) δ: 2.87 (3H, s), 4.13–4.16 (2H, m), 4.31–4.33 (2H, m),6.88 (1H, d, J=8 Hz), 7.50 (1H, d, J=9 Hz), 7.72–7.76 (1H, m), 9.64 (1H,s).

Description 15

5-(2-(Methanesulphonyloxy)ethoxy)-2-methylquinazoline (D15)

To a solution of 2-(2-methylquinazolin-5-yloxy)ethanol (0.330 g, 1.62mmol) in dichloromethane (20 mL) and triethylamine (0.34 mL, 2.43 mmol)was added methane sulfonyl chloride (0.14 mL, 1.78 mmol) dropwise. Thereaction mixture was allowed to stir at room temperature for 2 h. Thereaction mixture was diluted with further dichloromethane andpartitioned with saturated NaHCO₃ aq. The organic phase was washed withbrine, dried (MgSO₄) and evaporated in vacuo to give the title compoundas a cream solid (0.452 g, 99%).

Mass spectrum (ES⁺): Found 283 (MH⁺) C₁₂H₁₄N₂O₄S requires 282.

¹H NMR (CDCl₃) δ: 2.89 (3H, s), 3.10 (3H, s), 4.46–4.48 (2H, m).4.71–4.73 (2H, m), 6.86 (1H, d, J=8 Hz), 7.74–7.78 (1H, d, J=9 Hz),7.74–7.78 (1H, m), 9.69 (1H, s).

Description 16

2-(5-Quinolinyloxy)ethyl Bromide (D16)

A mixture of 5-hydroxyquinoline (0.3 g, 2.1 mmol), 1,2-dibromoethane(3.9 g, 21 mmol) and potassium carbonate (1.5 g, 11 mmol) in methylethyl ketone (15 mL) was allowed to stir at 85° C. for 24 h. The mixturewas evaporated in vacuo and the residue was partitioned between ether(200 mL) and water (200 mL). The organic layer was dried (Na₂SO₄) andevaporated in vacuo to give the title compound (0.53 g).

¹H NMR (CDCl₃) δ: 3.80 (2H, m), 4.49 (2H, m), 6.86 (1H, d, J=8 Hz), 7.41(1H, dd, J=8, 4 Hz), 7.61 (1H, t, J=8 Hz), 7.73 (1H, d, J=8 Hz), 8.64(1H, d, J=8 Hz), 8.91 (1H, m).

Description 17

5-Hydroxy-2-methylquinoline (D17)

A mixture of 2-methyl-5,6,7,8-tetrahydroquinolin-5-one [E. Reimann, J.Freisinger, Arch. Pharm. (Weinheim), 318, 871 (1985)] (0.57 g, 3.5 mmol)and 48% aqueous HBr (3.5 mL) was warmed to 60° C. and treated dropwisewith bromine (0.19 mL, 0.59 g, 3.6 mmol), with vigorous stirring. Theresulting mixture was stirred at 60° C. for 1 h, then evaporated invacuo. The residue was treated with isopropanol with stirring, then themixture was evaporated in vacuo to give a waxy solid, which wastriturated with 1:1 isopropanol-ether to give a beige powder (0.9 g). Amixture of this material, lithium carbonate (0.48 g, 6.7 mmol), lithiumbromide (0.28 g, 3.2 mmol) and N,N-dimethylformamide (10 mL) was heatedat 150° C. under argon with stirring for 2 h. The mixture was cooledthen evaporated in vacuo. Chromatography of the residue on silica with0–100% ethyl acetate-hexane gradient elution gave the title compound(0.28 g, 49%) as a solid.

Mass spectrum (API⁺): Found 160 (MH⁺). C₁₀H₉NO requires 159.

Description 18

5-(2-Bromoethoxy)-2-methylquinoline (D18)

The title compound was prepared from 5-hydroxy-2-methylquinoline and1,2-dibromoethane using a similar procedure to Description 16, in 91%yield.

Mass spectrum (API⁺): Found 266 (MH⁺). C₁₂H₁₂ ⁷⁹BrNO requires 265.

Description 19

4-Hydroxy-3-nitrophenyl Benzoate (D19)

To a stirred solution of 4-hydroxyphenyl benzoate (10 g, 47 mmol) inacetic acid (250 mL) was added, dropwise with external ice-bath cooling,nitric acid (d=1.42, 2.9 mL) (T=10° C.). The mixture was warmed to 20°C. and stirred for a further 56 h. The solution was evaporated in vacuoand water added to the residue. The resulting yellow solid was collectedby filtration, washed with water and dried in vacuo to give the titlecompound (11.8 g, 97%).

¹H NMR (CDCl₃) δ: 7.23 (1H, d), 7.53 (3H, m), 7.67 (1H, m), 8.00 (1H,d), 8.17 (2H, m), 10.52 (1H, s).

Description 20

4-(Methoxycarbonylmethoxy)-3-nitrophenyl Benzoate (D20)

A mixture of 4-hydroxy-3-nitrophenyl benzoate (48.8 g, 0.19 mol), methylbromoacetate (28.8 g, 0.19 mol), anhydrous potassium carbonate (33.8 g,0.24 mol) and acetone (700 mL) was heated at reflux for 24 h. Themixture was evaporated in vacuo and the residue partitioned betweenaqueous NaOH (1 M, 1 L) and dichloromethane (3×200 mL). The combinedorganic extracts were washed with aqueous NaOH (1 M, 500 mL), water (500mL) and brine (250 mL), then dried (Na₂SO₄) and evaporated in vacuo togive a solid. Crystallisation from methanol following decolourisationwith charcoal gave the title compound (38 g, 61%) as pale yellowneedles.

¹H NMR (CDCl₃) δ: 3.83 (3H, s), 4.82 (2H, s), 7.08 (1H, d, J=9 Hz), 7.45(1H, dd, J=9, 2 Hz), 7.56 (2H, m), 7.67 (1H, m), 7.83 (1H, d, J=2 Hz),8.19 (2H, m).

Description 21

4-(Methoxycarbonylmethoxy)-3-nitrophenol (D21)

To a stirred suspension of 4-(methoxycarbonylmethoxy)-3-nitrophenylbenzoate (26.2 g, 79 mmol) in methanol (600 mL) at 20° C. was added,dropwise over 0.3 h, a solution of sodium methoxide (4.7 g, 87 mmol) inmethanol (300 mL). The resulting mixture was stirred at 20° C. for 2 hthen at 50° C. for 1 h. The solution was concentrated to 200 mL invacuo, then poured into water (1 L) and extracted with ether-hexane(1:5, 500 mL). The aqueous phase was neutralised with 2M hydrochloricacid, then extracted with dichloromethane (6×300 mL). The combineddichloromethane extracts were dried (Na₂SO₄) and evaporated in vacuo togive a semi-solid, which was triturated with diethyl ether-hexane (1:3,2×100 mL) to give the title compound (15.3 g, 85%) as a yellow solid.

¹H NMR (CDCl₃) δ: 2.00 (1H, br s), 3.80 (3H, s), 4.70 (2H, s), 6.95 (1H,d, J=9 Hz), 7.01 (1H, dd, J=9,2 Hz), 7.33 (1H, d, J=2 Hz).

Description 22

Methyl4-(4-(N-(t-butyloxycarbonyl)piperidinyl)oxy)-2-nitrophenoxyacetate (D22)

To a stirred solution of 4-(methoxycarbonylmethoxy)-3-nitrophenol (6.0g, 26.8 mmol), 1-(t-butyloxycarbonyl)-4-hydroxypiperidine (13.8 g, 68.9mmol) and triphenylphosphine (18.0 g, 68.9 mmol) in tetrahydrofuran (80mL) at 20° C. under argon was added diisopropyl azodicarboxylate (13.9g, 68.9 mmol), dropwise over 0.75 h. The resulting solution was stirredat 20° C. for 4 h, then evaporated in vacuo. Chromatography of theresidue on silica (400 g) eluting with 5–50% ether in hexane gave thetitle compound (10.1 g, 93%) as a yellow oil.

¹H NMR (CDCl₃) δ: 1.48 (9H, s), 1.65–2.00 (4H, m), 3.34 (2H, m), 3.69(2H, m), 3.81 (3H, s), 4.44 (1H, m), 4.72 (2H, s), 7.02 (1H, d, J=9 Hz),7.10 (1H, dd, J=9, 2 Hz), 7.43 (1H, d, J=2 Hz).

Description 23

6-(4-(N-(t-Butyloxycarbonyl)piperidinyl)oxy)-4H-benzo[1,4]oxazin-3-one(D23)

A mixture of methyl4-(4-(N-(t-butyloxycarbonyl)piperidinyl)oxy)-2-nitrophenoxyacetate (10.1g, 24.6 mmol), 10% palladium on carbon (1.0 g) and methanol (300 mL) washydrogenated at 20° C. and 1 bar for 4 h. Catalyst was removed byfiltration and the filtrate was evaporated in vacuo to give an oilyresidue, which was dissolved in toluene. The resulting solution washeated at reflux for 2 h then evaporated in vacuo. Chromatography of theresidue on silica with 25–100% ethyl acetate in hexane gave the titlecompound (7.2 g, 84%) as a colourless solid.

¹H NMR (CDCl₃) δ: 1.49 (9H, s), 1.74 (2H, m), 1.89 (2H, m), 3.02 (2H,m), 3.68 (2H, m), 4.34 (1H, m), 4.55 (2H, s), 6.44 (1H, d, J=2 Hz), 6.53(1H, dd, J=9, 2 Hz), 6.89 (1H, d, J=9 Hz), 8.82 (1H, br s).

Description 24

6-(4-Piperidinyloxy)-4H-benzo[1,4]oxazin-3-one hydrochloride (D24)

A mixture of6-(4-(N-(t-butyloxycarbonyl)piperidinyl)oxy)-4H-benzo[1,4]oxazin-3-one(3.78 g, 10.9 mmol), ethereal hydrogen chloride (50 mL) anddichloromethane (20 mL) was heated at 40° C. for 2 h, then allowed tostir at 20° C. for 18 h. The resulting colourless solid was collected byfiltration to give the title compound (2.72 g, 88%).

¹H NMR (CD₃OD) δ: 1.95–2.25 (4H, m), 3.24 (2H, m), 3.40 (2H, m), 4.53(2H, s), 4.60 (1H, m), 6.60 (1H, d, J=2 Hz), 6.65 (1H, dd, J=9, 2 Hz),6.92 (1H, d, J=9 Hz).

Description 25

8-(4-Piperidinyloxy)-4H-benzo[1,4]oxazin-3-one hydrochloride (D25)

The title compound was prepared using analogous routes and intermediatesto those used in the preparation of6-(4-piperidinyloxy)-4H-benzo[1,4]oxazin-3-one, hydrochloride.

Description 26

7-Fluoro-5-hydroxy-2-methylquinoline Hydrobromide (D26)

Crotonaldehyde (28 mL, 0.33 mol) was added dropwise to a refluxingsolution of 3,5-difluoroaniline (10.75 g, 0.083 mol) in 5 N hydrochloricacid (450 mL) and reflux was continued for a further 0.5 h. Reactionmixture was cooled, diluted with water (200 mL) and washed with ether(200 mL). The aqueous layer was basified (pH 14) with 50% NaOH (aq) andextracted into dichloromethane (3×200 mL). The combined organic phaseswere dried (Na₂SO₄) and evaporated in vacuo to give a dark oil which waspurified by chromatography on silica gel (˜100 g) with 50–100% ethylacetate in hexane gradient elution to give5,7-difluoro-2-methylquinoline as a brown solid (6.57 g, 44%). A mixtureof 5,7-difluoro-2-methylquinoline (1.0 g, 5.6 mmol) and sodium methoxide(1.62 g, 30 mmol) in methanol (50 mL), was stirred at reflux for 18 h,cooled, and most of the methanol removed in vacuo. The residue waspartitioned between ethyl acetate (100 mL), and water (100 mL). Theorganic phase was dried (Na₂SO₄) and evaporated in vacuo to give a brownoil which was purified by chromatography on silica gel (˜60 g) with20–30% ethyl acetate hexane gradient elution to give a yellow solid(0.57 g) which was suspended in 48% HBr (aq) (5 mL) and heated at refluxfor 18 h. Reaction mixture was cooled and evaporated in vacuo to givethe title compound as a brown solid (0.67 g, 46%).

Mass spectrum (API⁺): Found 178 (MH⁺). C₁₀H₈FNO requires 177.

Description 27

5-(2-Bromoethoxy)-7-fluoro-2-methylquinoline (D27)

The title compound was prepared from7-fluoro-5-hydroxy-2-methylquinoline hydrobromide and 1,2-dibromoethaneusing a similar procedure to Description 16, in 91% yield.

Description 28

8-Chloro-5-hydroxy-2-methylquinoline (D28)

Crotonaldehyde (17.5 mL, 0.21 mol) was added dropwise to a refluxingsolution of 2-chloro-5-methoxyaniline hydrochloride (10.36 g, 53.4 mmol)in 5 N hydrochloric acid (450 mL) and reflux continued for a further 0.5h. The reaction mixture was cooled and diluted with water (500 mL), thenextracted with ether (400 mL). The aqueous layer was separated andbasified using 50% aqueous NaOH (pH 14), and then extracted intodichloromethane (3×300 mL). The combined organic phases were dried(Na₂SO₄) and evaporated in vacuo to give a dark oil which was purifiedby chromatography on silica gel (˜200 g) eluting with 20% ethyl acetatein hexane to give a brown oil (5.17 g) which was heated at reflux in amixture of acetic acid (30 mL) and 48% hydrobromic acid (30 mL) for 66h. Reaction mixture was evaporated in vacuo and the residue suspended insat. NaHCO₃ (aq), then extracted into dichloromethane (3×50 mL). Thecombined organic phases were dried (Na₂SO₄) and evaporated in vacuo togive a brown solid (2.90 g, 28%).

Mass spectrum (API⁺): Found 194 (MH⁺). C₁₀H₈ ³⁵CINO requires 193.

Description 29

7-Chloro-5-hydroxy-2-methylquinoline (D29)

The title compound was prepared from 3-chloro-5-methoxyaniline using asimilar procedure to Description 28, in 26% yield.

Mass spectrum (API⁺): Found 194 (MH⁺). C₁₀H₈ ³⁵CINO requires 193.

Description 30

5-(2-Bromoethoxy)-7-chloro-2-methylquinoline (D30)

The title compound was prepared from7-chloro-5-hydroxy-2-methylquinoline and 1,2-dibromoethane using asimilar procedure to Description 16.

Mass spectrum (API⁺): Found 300 (MH⁺). C₁₂H₁₁ ⁷⁹Br³⁵CINO requires 299.

EXAMPLE 18-{1-[2-(2-Methylquinolin-5-yloxy)ethyl]piperidin-4-yloxy}-4H-benzo[1,4]oxazin-3-onehydrochloride (E1).

The title compound was prepared by reaction of8-(piperidin-4-yloxy)-4H-benzo[1,4]oxazin-3-one (0.225 g, 0.79 mmol),5-(2-bromoethoxy)-2-methylquinoline (0.220 g, 0.83 mmol) andN,N-diisopropylethylamine (0.41 mL, 2.37 mmol) in isopropyl alcohol (15mL). The mixture was heated at 90° C. with stirring for 124 h, thencooled and the isopropyl alcohol evaporated in vacuo. The residue waspartitioned between dichloromethane (15 mL), and water (15 mL). Theorganic layer was added onto a 20 g pre-packed silica column and elutedwith 0–10% methanol in ethyl acetate. Fractions containing desiredmaterial were combined and evaporated in vacuo to give the titlecompound (0.24 g, 69%) as a colourless solid.

Mass spectrum (APCI⁺): Found 434 (MH⁺). C₂₅H₂₇N₃O₄ requires 433.

¹H NMR (250 MHz, CDCl₃) free base δ: 2.07–1.85 (m, 4H), 2.55–2.45 (m,2H), 2.73 (s, 3H), 3.01–2.93 (m, 4H), 4.36–4.27 (m, 3H), 4.63 (s, 2H),6.47 (dd, 1H), 6.66 (dd, 1H), 6.89–6.79 (m, 2H), 7.25 (d, 1H), 7.63–7.52(m, 2H), 8.44 (d, 1H), 8.85 (s, 1H).

EXAMPLE 25-{2-[4-(3H-Benzimidazol-4-ylmethyl)piperazin-1-yl]ethoxy}-2-methylquinoline(E2).

A mixture of 2-methyl-5-(2-piperazin-1-ylethoxy)quinoline (0.04 g, 0.15mmol) and 3H-benzimidazole-4-carboxaldehyde (0.024 g, 0.15 mmol) in1,2-dichloroethane (5 mL) was treated with sodium triacetoxyborohydride(47 mg, 0.22 mmol) and stirred at 20° C. under an atmosphere of argonfor 24 h. The mixture was then treated with saturated aqueous NaHCO₃ (20mL) and the organic layer separated and purified directly bychromatography on silica (ethyl acetate to 10% methanol/ethyl acetate),to afford the title compound (0.013 g, 22%) as a solid.

Mass spectrum (APCI⁺): Found 402 (MH⁺). C₂₄H₂₇N₅O requires 401.

EXAMPLE 35-{4-[2-(2-Methylquinolin-5-yloxy)ethyl]piperazin-1-ylmethyl}quinoline(E3).

The title compound was prepared using the method described in Example 2.

Mass spectrum (APCI⁺): Found 413 (MH⁺). C₂₆H₂₈N₄O requires 412.

EXAMPLE 45-{4-[2-(2-Methylquinolin-5-yloxy)ethyl]piperazin-1-ylmethyl}quinoxaline(E4).

The title compound was prepared using the method described in Example 2.

Mass spectrum (APCI⁺): Found 414 (MH⁺). C₂₅H₂₇N₅O requires 413.

EXAMPLE 58-{1-[2-(2-Methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}4H-benzo[1,4]oxazin-3-one(E5)

The title compound was prepared from8-(piperidin-4-ylmethyl)-4H-benzo[1,4]oxazin-3-one and5-(2-bromoethoxy)-2-methylquinoline in a similar manner to Example 1.

Mass spectrum (API⁺): Found 432 (MH⁺). C₂₆H₂₉N₃O₃ requires 431.

¹H NMR (CDCl₃) δ: 1.25–1.40 (2H, m), 1.50–1.70 (3H, m), 2.10–2.20 (2H,m), 2.57 (2H, d, J=7 Hz), 2.72 (3H, s), 2.93 (2H, t, J=7 Hz), 3.00–3.08(2H, m), 4.27 (2H, t, J=6 Hz), 4.58 (2H, s), 6.63 (1H, d, J=8 Hz),6.75–6.85 (2H, m), 6.87 (1H, t, J=8 Hz), 7.23 (1H, d, J=8 Hz), 7.50–7.64(2H, m), 7.83 (1H, br. s), 8.42 (1H, d, J=8 Hz).

EXAMPLE 68-{1-[2-(7-Fluoro-2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}-4H-benzo[1,4]oxazin-3-one(E6)

The title compound was prepared from8-piperidin-4-ylmethyl-4H-benzo[1,4]oxazin-3-one and5-(2-bromoethoxy)-7-fluoro-2-methylquinoline in a similar manner toExample 1.

Mass spectrum (API⁺): Found 450 (MH⁺). C₂₆H₂₈FN₃O₃ requires 449.

¹H NMR (CDCl₃) δ: 1.25–1.40 (2H, m), 1.50–1.70 (3H, m), 2.10–2.20 (2H,m), 2.57 (2H, d, J=7 Hz), 2.70 (3H, s), 2.93 (2H, t, J=7 Hz), 3.00–3.08(2H, m), 4.24 (2H, t, J=6 Hz), 4.58 (2H, s), 6.59 (1H, dd, J=8, 2Hz),6.64 (1H, dd, J=8, 2 Hz), 6.80 (1H, d, J=8 Hz), 6.87 (1H, t, J=8 Hz),7.18 (1H, d, J=8 Hz), 7.22 (1H, dd, J=10, 2 Hz), 7.80 (1H, br. s), 8.35(1H, d, J=8 Hz).

EXAMPLE 78-{1-[2-(7-Chloro-2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}-4H-benzo[1,4]oxazin-3-one(E7)

The title compound was prepared from8-(piperidin-4-ylmethyl)-4H-benzo[1,4]oxazin-3-one and5-(2-bromoethoxy)-7-chloro-2-methylquinoline in a similar manner toExample 1.

Mass spectrum (API⁺): Found 466 (MH⁺). C₂₆H₂₈ ³⁵CIN₃O₃ requires 465.

¹H NMR (CDCl₃) δ: 1.25–1.41 (2H, m), 1.50–1.70 (3H, m), 2.10–2.20 (2H,m), 2.57 (2H, d, J=6 Hz), 2.70 (3H, s), 2.92 (2H, t, J=7 Hz), 3.00–3.06(2H, m), 4.24 (2H, t, J=6 Hz), 4.58 (2H, s), 6.66 (1H, d, J=8 Hz),6.73–6.85 (2H, m), 6.86(1H, t, J=8 Hz), 7.21 (1H, d, J=8 Hz), 7.59 (1H,s), 8.34 (1H, d, J=8 Hz), 8.57 (1H, br. s).

EXAMPLE 88-{1-[2-(2-Methylquinazolin-5-yloxy)ethyl]piperidin-4-ylmethyl}-4H-benzo[1,4]oxazin-3-one(E8)

The title compound was prepared from8-(piperidin-4-ylmethyl)-4H-benzo[1,4]oxazin-3-one and5-(2-(methanesulphonyloxy)ethoxy)-2-methylquinazoline in a similarmanner to Example 1.

Mass spectrum (API⁺): Found 433 (MH⁺). C₂₅H₂₈N₄O₃ requires 432. ¹H NMR(CDCl₃) δ: 1.25–1.40 (2H, m), 1.50–1.70 (3H, m), 2.10–2.20 (2H, m), 2.57(2H, d, J=7 Hz), 2.88 (3H, s), 2.94 (2H, t, J=6 Hz), 3.00–3.06 (2H, m),4.30 (2H, t, J=6 Hz), 4.58 (2H, s), 6.65 (1H, d, J=8 Hz), 6.75–6.95 (3H,m), 7.48(1H, d, J=8 Hz), 7.74(1H, t, J=8 Hz), 8.09 (1H, br. s), 9.63(1H, s).

EXAMPLE 94-Methyl-8-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}-4H-benzo[1,4]oxazin-3-one(E9)

The title compound was prepared from4-methyl-8-(piperidin-4-ylmethyl)4H-benzo[1,4]oxazin-3-one and5-(2-bromoethoxy)-2-methylquinoline in a similar manner to Example 1.

Mass spectrum (API⁺): Found 446 (MH⁺). C₂₇H₃₁N₃O₃ requires 445.

¹H NMR (CDCl₃) δ: 1.25–1.40 (2H, m), 1.45–1.70 (3H, m), 2.10–2.20 (2H,m), 2.58 (2H , d, J=7 Hz), 2.72 (3H, s), 2.93 (2H, t, J=6 Hz), 3.00–3.08(2H, m), 3.35 (3H, s), 4.27 (2H, t, J=6 Hz), 4.58 (2H, s), 6.79 (1H, d,J=8 Hz), 6.81 (2H, d, J=8 Hz), 6.96 (1H, t, J=7 Hz), 7.23 (1H, d, J=8Hz), 7.50–7.70 (2H, m), 8.43 (1H, d, J=8 Hz).

EXAMPLE 108-{1-[2-(7-Fluoro-2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}-4-methyl-4H-benzo[1,4]oxazin-3-one(E10)

The title compound was prepared from4-methyl-8-(piperidin-4-ylmethyl)-4H-benzo[1,4]oxazin-3-one and5-(2-bromoethoxy)-7-fluoro-2-methylquinoline in a similar manner toExample 1.

Mass spectrum (API⁺): Found 464 (MH⁺). C₂₇H₃₀FN₃O₃ requires 463.

¹H NMR (CDCl₃) δ: 1.25–1.40 (2H, m), 1.50–1.70 (3H, m), 2.10–2.20 (2H,m), 2.58 (2H, d, J=7 Hz), 2.70 (3H, s), 2.92 (2H, t, J=7 Hz), 2.98–3.05(2H, m), 3.35 (3H, s), 4.24 (2H, t, J=6 Hz), 4.58 (2H, s), 6.59 (1H, dd,J=8, 2Hz), 6.84 (2H, dd, J=8, 2 Hz), 6.96 (1H, t, J=8 Hz), 7.18 (1H, d,J=8 Hz), 7.23 (1H, dd, J=10,2 Hz), 8.35 (1H, d, J=8 Hz).

EXAMPLE 118-{1-[2-(7-Chloro-2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}-4-methyl-4H-benzo[1,4]oxazin-3-one(E1)

The title compound was prepared from4-methyl-8-(piperidin-4-ylmethyl)-4H-benzo[1,4]oxazin-3-one and5-(2-bromoethoxy)-7-chloro-2-methylquinoline in a similar manner toExample 1.

Mass spectrum (API⁺): Found 480 (MH⁺). C₂₇H₃₀ ³⁵CIN₃O₃ requires 479.

¹H NMR (CDCl₃) δ: 1.25–1.41 (2H, m), 1.50–1.70 (3H, m), 2.05–2.20 (2H,m), 2.58 (2H, d, J=6 Hz), 2.71 (3H, s), 2.92 (2H, t, J=6 Hz), 2.98–3.04(2H, m), 3.35 (3H, s), 4.24 (2H, t, J=6 Hz), 4.58 (2H, s), 6.77 (1H, s),6.85 (2H, d, J=8 Hz), 6.96 (1H, t, J=8 Hz), 7.22 (1H, d, J=8 Hz), 7.59(1H, s), 8.34 (1H, d, J=8 Hz).

EXAMPLE 124-Methyl-8-{1-[2-(2-methylquinazolin-5-yloxy)ethyl]piperidin-4-ylmethyl}-4H-benzo[1,4]oxazin-3-one(E12)

The title compound was prepared from4-methyl-8-(piperidin-4-ylmethyl)-4H-benzo[1,4]oxazin-3-one and5-(2-(methanesulphonyloxy)ethoxy)-2-methylquinazoline in a similarmanner to Example 1.

Mass spectrum (API⁺): Found 447 (MH⁺). C₂₆H₃₀N₄O₃ requires 446. ¹H NMR(CDCl₃) δ: 1.27–1.40 (2H, m), 1.50–1.70 (3H, m), 2.10–2.20 (2H, m), 2.58(2H, d, J=7 Hz), 2.88 (3H, s), 2.94 (2H, t, J=6 Hz), 3.00–3.06 (2H, m),3.36 (3H, s), 4.30 (2H, t, J=6 Hz), 4.58 (2H, s), 6.88 (3H, m), 6.96(1H, t, J=8 Hz), 7.48 (1H, d, J=8 Hz), 7.74 (1H, t, J=8 Hz), 9.63 (1H,s).

1. A compound of formula (I) or a pharmaceutically acceptable saltthereof:

wherein: A is phenyl, naphthyl, indolyl, quinolinyl, quinazolinyl,indazolyl, isoquinolinyl or benzofuranyl; any of which is optionallysubstituted by 1 to 4 substituents, which may be the same or different,and which are selected from the following group: halogen, hydroxy,cyano, CF₃, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkoxyC₁₋₆alkyl,C₃₋₇cycloalkylC₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkylsulfonyl,C₁₋₆alkylsulfinyl, C₁₋₆alkylsulfonyloxy, C₁₋₆alkylsulfonylC₁₋₆alkyl,C₁₋₆alkylsulfonamido, C₁₋₆alkylamido, C₁₋₆alkylsulfonamidoC₁₋₆alkyl andC₁₋₆alkylamidoC₁₋₆alkyl; X is carbon, Y is CH and

 is a double bond; or X is CH, Y is CH₂ or oxygen and

 is a single bond; or X is nitrogen, Y is CH₂ and

 is a single bond; R1 is halogen, cyano, or C₁₋₆alkoxy; a is 0, 1, 2 or3; b is 0 or 1; R2 is hydrogen, C₁₋₆alkyl, C₁₋₆alkanoyl,fluoroC₁₋₆alkanoyl, C₁₋₆alkylsulfonyl, fluoroC₁₋₆alkylsulfonyl,carbamoyl, C₁₋₆alkylcarbamoyl or arylC₁₋₆alkyl; and R3, together withthe nitrogen atom to which it is attached, forms an optionallysubstituted benzoxazinone, benzoimidazolyl, quinoxalinyl or quinolinylgroup.
 2. A compound as claimed in claim 1, wherein A is quinolinyl orquinazolinyl.
 3. A compound as claimed in claim 2, wherein A is5-(2-methyl)quinolinyl or 5-(2-methyl)quinazolinyl.
 4. A compound asclaimed in claim 1, wherein R1 is fluoro.
 5. A compound as claimed inclaim 1, wherein a is 0, 1 or
 2. 6. A compound as claimed in claim 1,wherein when b is 1, R2 is hydrogen, C₁₋₆alkyl or C₁₋₆alkylsulfonyl. 7.A compound as claimed in claim 1 which is:8-{1-[2-(2-Methylquinolin-5-yloxy)ethyl]piperidin-4-yloxy}-4H-benzo[1,4]oxazin-3-onehydrochloride; 5-{2-[4-(3H-Benzimidazol-4-ylmethyl)piperazin-1-yl]ethoxy}-2-methylquinoline;5-{4-[2-(2-Methylquinolin-5-yloxy)ethyl]piperazin-1-ylmethyl}quinoline;5-{4-[2-(2-Methylquinolin-5-yloxy)ethyl]piperazin-1-ylmethyl}quinoxaline;8-{1-[2-(2-Methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}4H-benzo [1,4]oxazin-3-one;8-{1-[2-(7-Fluoro-2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}-4H-benzo[1,4]oxazin-3-one;8-{1-[2-(7-Chloro-2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}-4H-benzo[1,4]oxazin-3-one;8-{1-[2-(2-Methylquinazolin-5-yloxy)ethyl]piperidin-4-ylmethyl}-4H-benzo[1,4]oxazin-3-one;4-Methyl-8-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}-4H-benzo[1,4]oxazin-3-one;8-{1-[2-(7-Fluoro-2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}-4-methyl-4H-benzo[1,4]oxazin-3-one;8-{1-[2-(7-Chloro-2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}-4-methyl-4H-benzo[1,4]oxazin-3-one;4-Methyl-8-{1-[2-(2-methylquinazolin-5-yloxy)ethyl]piperidin-4-ylmethyl}-4H-benzo[1,4]oxazin-3-one;or a pharmaceutically acceptable salt thereof.
 8. A process for thepreparation of the compound of formula (I) as claimed in claim 1 or apharmaceutically acceptable salt thereof, which process comprises: (a)the coupling of a compound of formula (II):

wherein A is as defined for formula (I) and L is a leaving group, with acompound of formula (III):

wherein a, b, R1, R2, R3, X, Y and

are as defined for formula (I); or (b) for a compound wherein X isnitrogen, the coupling of a compound of formula (IV):

wherein A is as defined for formula (I), with a compound of formula (V):

wherein a, b, R1, R2 and R3 are as defined for formula (I); andthereafter optionally for process (a) or process (b): removing anyprotecting groups and/or converting the compound of formula (I) intoanother compound of formula (I) or forming a pharmaceutically acceptablesalt.
 9. A pharmaceutical composition comprising the compound as claimedin claim 1 and a pharmaceutically acceptable diluent, carrier orexcipient.
 10. A process for preparing a pharmaceutical compositioncomprising mixing the compound according to claim 1 and apharmaceutically acceptable carrier or excipient.
 11. A method oftreating depression or anxiety which comprises administering to apatient in need thereof a safe and therapeutically effective amount ofthe compound as defined in claim
 1. 12. A method of treating depressionor anxiety which comprises administering to a patient in need thereof asafe and therapeutically effective amount of the composition as definedin claim 9.